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* From the School of Medicine and Pharmacology (Dr. Waterer), University of Western Australia, Perth, WA, Australia; Physicians Research Network (Dr. Kessler), Methodist Le Bonheur Healthcare, Memphis, TN; and Division of Pulmonary and Critical Care (Dr. Wunderink), Feinberg School of Medicine, Northwestern University, Evanston, IL.
Correspondence to: Grant W. Waterer, FCCP, University of Western Australia, School of Medicine and Pharmacology, 4th Floor MRF Building, Royal Perth Hospital, GPO Box X2213, Perth, WA, Australia 6847; e-mail waterer{at}cyllene.uwa.edu.au
Abstract
Objectives: The time to the first antibiotic dose (TFAD) has been adopted as a measure of quality of care in patients with community-acquired pneumonia (CAP) based on two retrospective studies of large Medicare databases. The mechanism by which a difference of a few hours in receiving antibiotics can be deleterious is difficult to understand given the historical data regarding how long it takes for antibiotics to influence outcome. We investigated the factors that predict a prolonged TFAD and their association with mortality.
Design: Prospective cohort study.
Setting: A large tertiary hospital.
Patients: Immunocompetent adults admitted to the hospital with CAP.
Results: A total of 451 patients with CAP were studied. A TFAD of > 4 h was associated with increased mortality (p = 0.017). Altered mental state (p = 0.001), absence of fever (p = 0.02), absence of hypoxia (p = 0.025), and increasing age (p = 0.038) were significant predictors of a TFAD of > 4 h. After adjusting for these factors, the association between TFAD and mortality was not statistically significant (p = 0.131). Similar findings were observed in patients who were 
65 years.
Conclusions: A delay in administering antibiotics in patients with CAP is more common in patients who present with an altered mental state or minimal signs of sepsis. TFAD is likely to be a marker of comorbidities driving both an atypical presentation and mortality rather than directly contributing to outcome. Using TFAD as an indicator of quality of care in patients with CAP without significant additional clinical information is potentially misleading as the relationships among TFAD, comorbidities, and outcome are complex.
Key Words: age • altered mental state • antibiotics • community-acquired pneumonia • presentation • time
Community-acquired pneumonia (CAP) is a major health problem in the United States. As well as being the seventh leading cause of death, the estimated financial cost of treating CAP in the United States exceeds 12 billion dollars per year.1
Two retrospective analyses23 of large Medicare databases identified the time between presentation to the hospital and the time to the first antibiotic dose (TFAD) as a significant predictor of outcome. Both of these studies have inconsistencies, particularly the higher mortality rate among those receiving antibiotics within 2 h. However, the findings of these studies have convinced national regulatory bodies in the United States to make TFAD a benchmark for quality of care in patients with CAP.4
A reasonable biological explanation for why a difference of a few hours in antibiotic administration should lead to a better outcome has not been established. Historical data strongly indicate that antibiotics take several days to impact on outcome from pneumococcal pneumonia.5 Possible explanations include confounding factors inadequately accounted for in the retrospective database reviews and TFAD being a surrogate marker for other quality-of-care factors.
While the use of large Medicare databases has advantages with respect to statistical power and the ability to generalize findings across broader populations, clear disadvantages occur with respect to the loss of detailed individual clinical data and the loss of surety of diagnosis inherent in prospective clinical trials. We analyzed our prospectively collected cohort of patients with CAP specifically examining the clinical factors influencing TFAD.
Materials and Methods
Study Design
A prospective cohort of patients admitted to the Methodist Healthcare-Memphis Hospitals with CAP between November 1998 and July 2001 was recruited. Informed consent was obtained from all patients. The Methodist Healthcare Institutional review board approved the study.
Inclusion Criteria
Consistent with published guidelines,6 CAP was defined as an acute illness (< 14 days of symptoms) in which the presence of a new chest radiographic infiltrate was confirmed by either a radiologist or a pulmonary/critical care physician, and having clinical features suggestive of acute pneumonia. The clinical features required for diagnosis were one feature from group A (fever [temperature of > 37.8°C], hypothermia [temperature of < 36°C], cough, and sputum production), or two features from group B (dyspnea, pleuritic pain, physical findings of lung consolidation, and leukocyte count of > 12 x 10 cells/L or < 4.5 x 10 cells/L).
Exclusion Criteria
Exclusion criteria included patients with HIV infection, those receiving chemotherapy or who had received immunosuppressive therapy in the past 60 days (including prednisolone, 20mg/d for > 7 days), nonambulatory nursing home residents, and patients who have been hospitalized within the past 30 days.
Definitions
The TFAD was defined as the time difference between the recorded time on presentation to triage in the emergency department and the recorded time of administration of the first dose of antibiotics by the nursing staff. Pneumonia severity index (PSI) scores7 were calculated at the time of the patient’s admission to the hospital. Septic shock was defined using American College of Chest Physicians/Society of Critical Care Medicine criteria.8 Hypoxia was defined as an oxygen saturation of < 90% while breathing room air. An altered mental state was defined as any disorientation in time, place, or person including any Glasgow coma scale score of < 15.
Statistical Analysis
Logistic regression analysis was used to assess the impact of clinical factors on TFAD. Significant interactions were included in all models at a threshold of p < 0.1. Analysis was performed using a statistical software package (SPSS, version 11.5.0; SPPS Inc; Chicago, IL). A p value of < 0.05 was considered to be significant.
Results
A total of 451 patients were enrolled into the study. The cohort had a mean (±SD) age of 58.2 ± 19.2 years, 53.3% were women, and the severity breakdown by PSI grade was as follows: grade I, 11.3%; grade II, 22.2%; grade III, 18.9%; grade IV, 20.4%; and grade V, 8.7%. The mean TFAD was 285 ± 202 min, with 50.7% of patients not receiving their first dose within 4 h. Of those patients with a TFAD of < 4 h, 32.0% were given antibiotics within 2 h of presentation. Death occurred in 36 patients (8.0%).
We next analyzed the data points on the PSI predicting a TFAD of > 4 h. Table 1 summarizes the significant findings. Various age cutoffs were assessed, but none performed better than treating age as a continuous variable. We also analyzed the predictors of antibiotic delivery in < 2 h. Significant predictors were the presence of shock (odds ratio [OR], 3.63; 95% confidence interval [CI], 1.63 to 8.09), fever with a temperature of > 101.0°F (OR, 2.20; 95% CI, 1.31 to 5.43), and the presence of hypoxia (OR, 1.69; 95% CI, 1.04 to 2.75).
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65 years,23 we analyzed this subset of patients separately. A total of 158 patients were 65 years of age. In this cohort, there were 17 deaths (10.8%), and 71 patients (44.9%) received antibiotics after 4 h. In those patients aged 65, an altered mental state remained a significant predictor of TFAD of > 4 h (OR, 3.2; 95% CI, 1.4 to 6.1). As seen in the univariate analysis presented in Table 4
, a TFAD of > 4 h approached statistical significance as a predictor of mortality, while the only statistically significant predictor was an altered mental state. In a multivariate analysis, a TFAD of > 4 h was not an independent predictor of mortality (p = 0.158) once an altered mental state (p = 0.02) was entered into the model.
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Using detailed clinical data from a prospectively collected cohort of patients with CAP, we have confirmed that a delay of > 4 h in receiving antibiotics is associated with adverse outcome. A delay of > 4 h is predicted by increasing age, the presence of an altered mental state, and the absence of significant fever or hypoxia. However, the association between TFAD and mortality is not straightforward as a delay in antibiotic administration is also associated with comorbid diseases that are very likely to be contributing to excess mortality. Our data also suggest that in elderly patients, and especially those presenting with confusion, physicians need to be more vigilant in excluding a diagnosis of pneumonia.
The association of a TFAD of > 4 h with an altered mental state and the absence of obvious signs of pneumonia, such as fever and hypoxia, have significant implications for the current recommendations for assessing the quality of care of patients with pneumonia. The Joint Commission of Health Care Organizations, the Centers for Medicare and Medicaid Services, and the National Quality Forum have adopted TFAD based on the findings from two studies of large Medicare databases that a delay of > 4 h2 or > 8 h3 was associated with an increased mortality. However, the fact that an altered mental state and the absence of fever were stronger predictors of mortality than a TFAD of > 4 h, combined with the multivariate analysis, suggest that a prolonged TFAD is more a marker for comorbidities that are responsible for both the increased mortality and atypical presentation. Particularly pertinent is the presence of an altered mental state, as this is associated not only with increased in-hospital mortality,9 but also with increased mortality after hospital discharge.10 An altered mental state may not only make it difficult for physicians to make a diagnosis, it may also delay presentation to hospital.
It is possible that an atypical presentation leads to a delay in the administration of antibiotics and that it is the delay that leads to increased mortality. However, historical data on the length of time that it takes for antibiotics to make an impact on outcome makes it unlikely that a difference of a few hours in administration will impact adversely on mortality,5 particularly as most patients have had symptomatic disease for several days. Furthermore, an altered mental state is associated with adverse in-hospital outcome11 and after-hospital outcome12 across a diverse range of medical conditions including noninfectious diseases. The adverse implications of an altered mental state are probably due to its association with increasing age and recognized or unrecognized comorbid illnesses, such as dementia.1112 Therefore, while there is no clear biological basis for why a difference of a few hours in administering antibiotics should have a direct affect on outcome, there is a cogent argument for comorbidities causing both an increased mortality and an atypical presentation of pneumonia, which lead to delayed recognition of pneumonia and a prolonged TFAD.
As TFAD is still a predictor of mortality regardless of whether it is causative or not, it may still be a useful quality-of-care marker as a surrogate marker for clinical acumen (with higher acumen being associated with an earlier diagnosis of pneumonia and therefore earlier treatment). Prolonged TFAD was associated with an atypical clinical presentation, suggesting that physicians do not consider pneumonia initially in patients who are unable to give a good history of respiratory tract illness or when signs of sepsis are absent. The observation that florid signs of sepsis were associated with the early administration of antibiotics further supports a prolonged TFAD as being a failure of recognition rather than a problem such as excess workload and failure to assess patients within a reasonable period of time.
If TFAD is used as a quality-of-care marker, it cannot be compared across institutions without good information on the proportion of patients who present with an altered mental state or an otherwise atypical presentation. Although captured by the PSI, this information is lost when only the total score is factored into the analysis.
The Medicare database studies23 were also limited by the fact that data were collected retrospectively and that key data points were not always available. As our study was prospective and patients were seen by an investigator within 24 h of presentation, we can be much more confident of the diagnosis of pneumonia and the relevant features of the clinical presentation. This may be particularly pertinent with respect to the recognition and documentation of an altered mental state in elderly patients.
As our study was conducted at a single site, the findings may not be able to be generalized to other institutions, which was the strength of the large Medicare database studies.23 However, evidence that altered mental state (or delirium) is underrecognized in emergency departments13 and that it leads to the misdiagnosis of the primary problem14 has been documented in other studies. An atypical presentation of pneumonia, particularly in the elderly, has also been reported as a factor contributing to delayed diagnosis,1516 suggesting that the issues we have identified are common ones.
Although we did not show a significant association between TFAD and mortality in the subset of patients > 65 years of age, this is most likely due to the low numbers of patients in the study. The fact that an altered mental state remained a significant predictor despite the low numbers adds further weight to the hypothesis that this is the key factor driving both mortality and a prolonged TFAD.
In conclusion, in a detailed prospective cohort of patients admitted to the hospital with CAP, we have found that the presence of an altered mental state and an atypical clinical presentation predict a delay of > 4 h in administering the first dose of antibiotics. While this delay was associated with an increased likelihood of adverse outcome, the most likely explanation is the impact of comorbidities on mortality rather than differences in the process or quality of medical care. While physicians need to be more alert to the possibility of pneumonia in patients presenting with an altered mental state, the major implication of our findings is that the widespread adoption of TFAD by regulatory bodies as a quality measure in treating patients with CAP is based on an incomplete understanding of the complexity of the relationships among TFAD, comorbidities, and outcome.
Footnotes
Abbreviations: CAP = community-acquired pneumonia; CI = confidence interval; OR = odds ratio; PSI = pneumonia severity index; TFAD = time to first antibiotic dose
No author has any conflict of interest with respect to this article.
Dr. Waterer is supported by the National Health and Medical Research Council of Australia.
Received for publication February 16, 2006. Accepted for publication February 25, 2006.
References
This article has been cited by other articles:
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  J. A. Welker, M. Huston, and J. D. McCue Antibiotic Timing and Errors in Diagnosing Pneumonia Arch Intern Med, February 25, 2008; 168(4): 351 - 356. [Abstract] [Full Text] [PDF]
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 Y.-H. Hsieh, R. E. Rothman, G. W. Waterer, and R. G. Wunderink Analytical Shortfalls in Multivariate Regression Analysis Chest, May 1, 2007; 131(5): 1613 - 1614. [Full Text] [PDF]
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 Mental Status Is a Predictor of Mortality in CAP Journal Watch Emergency Medicine, September 22, 2006; 2006(922): 4 - 4. [Full Text]
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 Examining the 4-Hour Rule for Pneumonia Treatment Journal Watch (General), August 29, 2006; 2006(829): 2 - 2. [Full Text]
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 Treatment of Pneumonia: Is Timing of Antibiotics a Quality Indicator? Journal Watch Infectious Diseases, August 23, 2006; 2006(823): 1 - 1. [Full Text]
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P. M. Houck Antibiotics and pneumonia: is timing everything or just a cause of more problems? Chest, July 1, 2006; 130(1): 1 - 3. [Full Text] [PDF]
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